Monovalent SARS-CoV-2 mRNA Vaccine Does not Boost Omicron-Specific Immune Response in Diabetic and Control Pediatric Patients.

While the immunogenicity of SARS-CoV-2 vaccines has been well described in adults, pediatric populations have been less studied. In particular, children with type 1 diabetes are generally at elevated risk for more severe disease after infections, but are understudied in terms of COVID-19 and SARS-CoV-2 vaccine responses. We investigated the immunogenicity of COVID-19 mRNA vaccinations in 35 children with type 1 diabetes (T1D) and 23 controls and found that these children develop levels of SARS-CoV-2 neutralizing antibody titers and spike protein-specific T cells comparable to nondiabetic children. However, in comparing the neutralizing antibody responses in children who received 2 doses of mRNA vaccines (24 T1D; 14 controls) with those who received a third, booster dose (11 T1D; 9 controls), we found that the booster dose increased neutralizing antibody titers against ancestral SARS-CoV-2 strains but, unexpectedly, not Omicron lineage variants. In contrast, boosting enhanced Omicron variant neutralizing antibody titers in adults.

Inspiring New Science to Guide Healthcare in Turner Syndrome: Rationale, design, and methods for the InsighTS Registry.

Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) Registry is a national, multicenter registry for individuals with Turner syndrome (TS) designed to collect and store validated longitudinal clinical data from a diverse cohort of patients with TS. Herein, we describe the rationale, design, and approach used to develop the InsighTS registry, as well as the demographics of the initial participants to illustrate the registry's diversity and future utility. Multiple stakeholder groups have been involved from project conceptualization through dissemination, ensuring the registry serves the priorities of the TS community. Key features of InsighTS include recruitment strategies to facilitate enrollment of participants that appropriately reflect the population of individuals with TS receiving care in the US, clarity of data ownership and sharing, and sustainability of this resource. The registry gathers clinical data on diagnosis, treatment, comorbidities, health care utilization, clinical practices, and quality of life with the goal of improving health outcomes for this population. Future directions include multiple patient-centered clinical-translational research projects that will use the InsighTS platform. This thorough and thoughtful planning will ensure InsighTS is a valuable and sustainable resource for the TS community for decades to come.

Screening for Turner syndrome-associated hyperglycemia: Evaluating hemoglobin A1c and fasting blood glucose.

INTRODUCTION: Individuals with Turner syndrome (TS) are at increased risk of developing diabetes mellitus (DM). Currently, annual DM screening with hemoglobin A1c (HbA1c) with or without fasting blood glucose (FBG) is recommended starting at age 10. However, the optimal DM screening for individuals with TS is not known. The purpose of this study was to evaluate the correlation between HbA1c, FBG, and the 2-hour oral glucose tolerance test (OGTT). A second goal was to query whether optimal HbA1c and fasting (FBG) cut points for TS-associated DM and impaired glucose tolerance (IGT), as defined by the OGTT 2-hour blood glucose (BG), might differ from those for the general population. METHODS: Individuals with TS ≥ age 10 from the TS: Genotype Phenotype study in the National Institute of Child Health and Human Development's Data and Specimen Hub (DASH) who had 2-hour OGTT BG, HbA1c, and FBG were included. Correlations between HbA1c, FBG, and 2-hour OGTT BG were evaluated. Areas under the receiver operative characteristic (ROC-AUC) curves were generated. Optimal cut points for predicting TS-associated IGT (2-hour BG ≥ 7.77 mmol/L ) and DM 2-hour BG ≥11.10 mmol/L) were determined. RESULTS: 348 individuals had complete data (2-hour OGTT BG < 7.77 mmol/L, n = 239; TS-associated IGT, n = 79; DM, n = 30). ROC-AUC was poor for HbA1c to predict IGT (0.57, 0.49-0.65) but better for DM (0.81, 0.71-0.90). ROC-AUC was also poor for FBG to predict IGT (0.63, 0.56-0.70) but better for DM (0.85, 0.77-0.93). At a cut point of 38 mmol/mol (5.6%), HbA1c had 67% sensitivity (95% CI: 47-83%) and 86% specificity (95% CI: 82-90%) for identifying TS-associated DM defined by 2-hour OGTT BG. DISCUSSION/CONCLUSIONS: The correlation of HbA1c and 2-hour OGTT BG are lower in TS than other published studies regarding type 2 DM. HbA1c is fairly specific for DM in TS but lacks sensitivity especially at currently utilized levels. Future research should focus on characterizing individuals with TS whose glycemic status is discordant, as this may provide additional insights into the pathophysiology of glucose metabolism in TS. Longitudinal assessement of glycemia as it relates to micro- and macrovascular complications in individuals with TS will further inform DM screening in this population.

CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome.

Turner syndrome (TS) is a chromosomal disorder caused by complete or partial loss of the second sex chromosome and exhibits phenotypic heterogeneity, even after accounting for mosaicism and karyotypic variation. Congenital heart defects (CHD) are found in up to 45 percent of girls with TS and span a phenotypic continuum of obstructive left-sided lesions, with bicuspid aortic valve (BAV) being the most common. Several recent studies have demonstrated a genome-wide impact of X chromosome haploinsufficiency, including global hypomethylation and altered RNA expression. The presence of such broad changes to the TS epigenome and transcriptome led others to hypothesize that X chromosome haploinsufficiency sensitizes the TS genome, and several studies have demonstrated that a second genetic hit can modify disease susceptibility in TS. The objective of this study was to determine whether genetic variants in known heart developmental pathways act synergistically in this setting to increase the risk for CHD, specifically BAV, in TS. We analyzed 208 whole exomes from girls and women with TS and performed gene-based variant enrichment analysis and rare-variant association testing to identify variants associated with BAV in TS. Notably, rare variants in CRELD1 were significantly enriched in individuals with TS who had BAV compared to those with structurally normal hearts. CRELD1 is a protein that functions as a regulator of calcineurin/NFAT signaling, and rare variants in CRELD1 have been associated with both syndromic and non-syndromic CHD. This observation supports the hypothesis that genetic modifiers outside the X chromosome that lie in known heart development pathways may influence CHD risk in TS.

Hyperglycemia in Turner syndrome: Impact, mechanisms, and areas for future research.

Turner syndrome (TS) is a common chromosomal disorder resulting from complete or partial absence of the second sex chromosome. Hyperglycemia, ranging from impaired glucose tolerance (IGT) to diabetes mellitus (DM), is common in TS. DM in individuals with TS is associated with an 11-fold excess in mortality. The reasons for the high prevalence of hyperglycemia in TS are not well understood even though this aspect of TS was initially reported almost 60 years ago. Karyotype, as a proxy for X chromosome (Xchr) gene dosage, has been associated with DM risk in TS - however, no specific Xchr genes or loci have been implicated in the TS hyperglycemia phenotype. The molecular genetic study of TS-related phenotypes is hampered by inability to design analyses based on familial segregation, as TS is a non-heritable genetic disorder. Mechanistic studies are confounded by a lack of adequate TS animal models, small and heterogenous study populations, and the use of medications that alter carbohydrate metabolism in the management of TS. This review summarizes and assesses existing data related to the physiological and genetic mechanisms hypothesized to underlie hyperglycemia in TS, concluding that insulin deficiency is an early defect intrinsic to TS that results in hyperglycemia. Diagnostic criteria and therapeutic options for treatment of hyperglycemia in TS are presented, while emphasizing the pitfalls and complexities of studying glucose metabolism and diagnosing hyperglycemia in the TS population.

Diabetes Device Downloading: Benefits and Barriers Among Youth With Type 1 Diabetes.

BACKGROUND: The majority of youth with type 1 diabetes (T1D) fail to meet glycemic targets despite increasing continuous glucose monitoring (CGM) use. We therefore aimed to determine the proportion of caregivers who review recent glycemic trends ("retrospective review") and make ensuant insulin adjustments based on this data ("retroactive insulin adjustments"). We additionally considered that fear of hypoglycemia and frequency of severe hypoglycemia would be associated with performing retrospective review. METHODS: We conducted a cross-sectional survey of caregivers of youth with T1D, collecting demographics, diabetes technology usage, patterns of glucose data review/insulin dose self-adjustment, and Hypoglycemia Fear Survey (HFS). RESULTS: Nineteen percent of eligible caregivers (191/1003) responded. Performing retrospective review was associated with younger child age (12.2 versus 15.4, P = .0001) and CGM use (92% versus 73%, P = .004), but was not associated with a significant improvement in child's HbA1c (7.89 versus 8.04, P = .65). Retrospective reviewers had significantly higher HFS-behavior scores (31.9 versus 27.7, P = .0002), which remained significantly higher when adjusted for child's age and CGM use (P = .005). Linear regression identified a significant negative association between HbA1c (%) and number of retroactive insulin adjustments (0.24 percent lower mean HbA1c per additional adjustment made, P = .02). CONCLUSIONS: Retrospective glucose data review is associated with improved HbA1c when coupled with data-driven retroactive insulin adjustments. Barriers to data downloading existed even in this cohort of predominantly CGM-using T1D families.

Hypoglycemia secondary to insulinoma masking the onset of type 1 diabetes in an adolescent.

Type 1 diabetes and insulinoma can co-occur in pediatric patients and may present with episodes of hypo- and hyperglycemia, significant glycemic variability, and weight gain. Surgical resection leads to development of fulminant diabetes.

Diabetic ketoacidosis drives COVID-19 related hospitalizations in children with type 1 diabetes.

BACKGROUND: Diabetes is a risk factor for poor COVID-19 outcomes, but pediatric patients with type 1 diabetes are poorly represented in current studies. METHODS: T1D Exchange coordinated a US type 1 diabetes COVID-19 registry. Forty-six diabetes centers submitted pediatric cases for patients with laboratory confirmed COVID-19. Associations between clinical factors and hospitalization were tested with Fisher's Exact Test. Logistic regression was used to calculate odds ratios for hospitalization. RESULTS: Data from 266 patients with previously established type 1 diabetes aged <19 years with COVID-19 were reported. Diabetic ketoacidosis (DKA) was the most common adverse outcome (n = 44, 72% of hospitalized patients). There were four hospitalizations for severe hypoglycemia, three hospitalizations requiring respiratory support (one of whom was intubated and mechanically ventilated), one case of multisystem inflammatory syndrome in children, and 10 patients who were hospitalized for reasons unrelated to COVID-19 or diabetes. Hospitalized patients (n = 61) were more likely than nonhospitalized patients (n = 205) to have minority race/ethnicity (67% vs 39%, P < 0.001), public insurance (64% vs 41%, P < 0.001), higher A1c (11% [97 mmol/mol] vs 8.2% [66 mmol/mol], P < 0.001), and lower insulin pump and lower continuous glucose monitoring use (26% vs 54%, P < 0.001; 39% vs 75%, P < 0.001). Age and gender were not associated with risk of hospitalization. Higher A1c was significantly associated with hospitalization, with an odds ratio of 1.56 (1.34-1.84) after adjusting for age, gender, insurance, and race/ethnicity. CONCLUSIONS: Higher A1c remained the only predictor for hospitalization with COVID-19. Diabetic ketoacidosis is the primary concern among this group.

The Evolution of Insulin Administration in Type 1 Diabetes.

Insulin has been utilized in the treatment of type 1 diabetes (T1D) for 100 years. While there is still no cure for T1D, insulin administration has undergone a remarkable evolution which has contributed to improvements in quality of life and life expectancy in individuals with T1D. The advent of faster-acting and longer-acting insulins allowed for the implementation of insulin regimens more closely resembling normal insulin physiology. These improvements afforded better glycemic control, which is crucial for limiting microvascular complications and improving T1D outcomes. Suspension of insulin delivery in response to actual and forecasted hypoglycemia has improved quality of life and mitigated hypoglycemia without compromising glycemic control. Advances in continuous glucose monitoring (CGM) and insulin pumps, efforts to model glucose and insulin kinetics, and the application of control theory to T1D have made the automation of insulin delivery a reality. This review will summarize the past, present, and future of insulin administration in T1D.

COVID-19 Hospitalization in Adults with Type 1 Diabetes: Results from the T1D Exchange Multicenter Surveillance Study.

CONTEXT: Diabetes mellitus is associated with increased COVID-19 morbidity and mortality, but there are few data focusing on outcomes in people with type 1 diabetes. OBJECTIVE: The objective of this study was to analyze characteristics of adults with type 1 diabetes for associations with COVID-19 hospitalization. DESIGN: An observational multisite cross-sectional study was performed. Diabetes care providers answered a 33-item questionnaire regarding demographics, symptoms, and diabetes- and COVID-19-related care and outcomes. Descriptive statistics were used to describe the study population, and multivariate logistic regression models were used to analyze the relationship between glycated hemoglobin (HbA1c), age, and comorbidities and hospitalization. SETTING: Cases were submitted from 52 US sites between March and August 2020. PATIENTS OR OTHER PARTICIPANTS: Adults over the age of 19 with type 1 diabetes and confirmed COVID-19 infection were included. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Hospitalization for COVID-19 infection. RESULTS: A total of 113 cases were analyzed. Fifty-eight patients were hospitalized, and 5 patients died. Patients who were hospitalized were more likely to be older, to identify as non-Hispanic Black, to use public insurance, or to have hypertension, and less likely to use continuous glucose monitoring or insulin pumps. Median HbA1c was 8.6% (70 mmol/mol) and was positively associated with hospitalization (odds ratio 1.42, 95% confidence interval 1.18-1.76), which persisted after adjustment for age, sex, race, and obesity. CONCLUSIONS: Baseline glycemic control and access to care are important modifiable risk factors which need to be addressed to optimize care of people with type 1 diabetes during the worldwide COVID-19 pandemic.

Candidate modifier genes for immune function in 22q11.2 deletion syndrome.

BACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS) is the most common contiguous microdeletion affecting humans and exhibits extreme phenotypic heterogeneity. Patients can manifest any combination of comorbidities including congenital heart disease, hypoparathyroidism, cleft palate, kidney abnormalities, neurodevelopmental disorders, and immune dysfunction. Immunodeficiency is present in the majority of patients with 22q11.2DS and is the second leading cause of death in these patients. Knowing the genetic determinants of immune dysfunction will aid in prognostication and potentially novel treatments. METHODS: We performed exome sequencing and gene-based variant association analysis on 31 deeply phenotyped individuals with the canonical 3Mb 22q11.2 deletion to identify what genes outside the 22q11.2 locus may be modifying the immune dysregulated phenotype. Immunophenotyping was performed using preexisting medical data and a novel scoring system developed from numerous clinical laboratory values including immunoglobulin levels, lymphocyte transformation to antigens (LTA), lymphocyte transformation to mitogens (LTM), and peripheral blood flow cytometry. Immunophenotypic scoring was validated against newborn screening T-cell receptor excision circle (TREC) results. RESULTS: Rare DNA variants in transcriptional regulators involved in retinoic acid signaling (NCOR2, OMIM *600848 and EP300, OMIM *602700) were found to be associated with immunophenotype. CONCLUSION: The expression of TBX1, which seems to confer the major phenotypic features of 22q11.2DS, is regulated via retinoic acid signaling, and alterations in retinoic acid signaling during embryonic development can lead to phenocopies of 22q11.2DS. These observations support the hypothesis that genetic modifiers outside the microdeletion locus may influence the immune function in 22q11.2DS patients.